Discussing the Unmet Clinical Needs in 2 Special CLL Patient Groups | Silvia Deaglio, MD | EHA 2024

Hello, my name is Silvia De Aglia. I work at the University of Turin in Northwest Italy and I'm a medical geneticist. Today I was at the CLL educational session and we talked about the new frontiers or the young men clinical needs in CLL. And essentially we discussed about two patients of populations, the patients that are so-called double resistant. So the patients during the course of their treatment acquire resistance to both BTK inhibitors and BCL2 inhibitors. And for them today it's unclear how they should be treated and what drugs they will likely respond to. And the second set of patients representing an unmet clinical need is those who undergo the so-called Richter transformation. So the evolution of CLL into a diffuse large B-cell lymphoma. When this lymphoma is clonally related, so it's similar to the CLL cell of origin, it's very difficult to treat because it does not respond to therapies that are conventionally used for lymphoma patients. And so also for this patient sub that there is dire need of new therapeutic strategies. And so while many people have studied the genetic underlying transformation of CLL into we discussed the functional pathways that are modulated focusing on rewiring of the metabolic machinery and of the apoptotic machinery. In fact there is a lot of evidence that during transformation CLL cells become better performing in terms of metabolism. They can uptake more glucose, they can eat up more sugar, they can make more DNA building which means that they can proliferate and also their mitochondria are better performance so their oxygen consumption rate increases. So what is interesting is that if you compare metabolic profiles of CLL cells and of patients that have aggressive CLL or Richter syndrome, you will find that their metabolism in the latter patients is increased, both in the enzymes that make up the TCA cycle and in the enzymes that are involved in glutamine metabolism. And so we asked what is behind this metabolic adaptation and we have investigated the role of an oncogene which is recurrently mutated in CLL patients and in one in three of Richter syndrome patients which is called Notch1. And we highlighted a functional relationship between the presence of Notch1 mutation and metabolic adaptation. So the CLL cells that carry Notch1 mutations are enriched in metabolic pathways at the gene expression profiles and when you go and look at them functionally they can perform glycolysis better and their mitochondria are more performing, they have bigger mitochondria and a higher mitochondrial mass. And this is true in a cell line model that we have set up but also in primary CLL taken from real patients that carry Notch1 mutations. Now can this be exploited therapeutically? At the moment it is so-so. There are no approved drugs that target metabolism in CLL but there are different groups around the world that are actively testing different drugs that interfere with metabolic pathways. The second pathway that is very important during transformation to Richter and aggressive CLL is apoptosis. Apoptosis is programmed cell death and it's regulated by a very complex web of molecules. There are some pro-apoptotic molecules and some anti-apoptotic molecules. And what happens in CLL cells is that there is a dominant anti-apoptotic molecule which is called BCL2. So there are in therapy and they are very effective BCL2 inhibitors. Now what happens is that when these cells become aggressive and when they transform to Richter they can either lose the expression BCL2 or become less dependent on BCL2. And so we study the dependency of these aggressive cells on other anti-apoptotic molecules, the most important of which is called MCL1. And we've also proposed some strategies to co-target MCL1 and BCL2. Strategies that have been, that have proved functional in mouse models so far. So at the end of my talk I also discussed the current limitations that we are facing when we are performing these kind of studies which are technical because we rely on primary cells and somehow primary cells from special, if you want, CLL patients with aggressive disease or with Richter syndrome are very hard to find. And so the results are difficult to compare standardized among labs. There are very few lines and the mouse models are not so good because they either have a fixed set of genetic mutations or they are immunocompromised and lack the microenvironment. And for this reason it may be that special systems to culture cells in scaffolds, in mechanic scaffolds that can recreate the microenvironment that happens in vivo in the lymph nodes may be beneficial. The other limitation is conceptual because so far, possibly because of our technical limitations, we have used not so much an unbiased approach as an educated guess approach. So most scientists have been studying their favorite gene or their favorite molecule in the disease. We should probably take a step back and try to see whether we can study the disease in an unbiased fashion in order to see whether there are prominent pathways and possible therapeutic vulnerabilities that can emerge.